DIET AND LIVER METABOLISM DETERMINE BRAIN METABOLISM OF NUTRITIONALLY ESSENTIAL POLYUNSATURATED FATTY ACIDS A coherent mathematical model, based on experimental studies in rodents, showed how brain composition and metabolism of the polyunsaturated fatty acids (PUFAs), DHA and arachidonic acid (AA), are regulated by their dietary intake and/or liver synthesis from their respective PUFAs, alpha-LA (18:3n-3) and LA (18:2n-6). In the absence of dietary DHA, but with sufficient dietary alpha-LNA (4.5% of total fatty acids), the rat liver can maintain a normal brain DHA content by synthesizing up to 45 times more DHA than the brain consumes. Rates of incorporation of circulating DHA and AA into brain, determined with quantitative autoradiography in unanesthetized rodents and with positron emission tomography (PET) in humans, equal respective rates of consumption within brain. The adult human brain consumes AA and DHA at rates of 17.8 and 4.6 mg/day, respectively. AA consumption does not change significantly with human aging (Ref. 1, 2 and 6). DIETARY N-6 PUFA DEPRIVATION IN ADULT RATS AA is critical to brain and body function, but few studies have examined effects of short-term dietary n-6 PUFA deprivation in rodents. We showed how such deprivation alters brain lipid composition and metabolism. Adult rats were fed for 15 weeks an n-6 PUFA adequate or deficient diet. Neither contained AA or docosahexaenoic acid. Linoleic acid, the precursor of AA, was reduced in the deficient but not adequate diet. The deficient compared with adequate diet reduced testes weight and AA concentrations in brain, liver, heart and testes, but increased n-3 PUFA concentrations in these organs. The testes changes may reflect involvement of AA and cPLA2 in testicular development and fertility (Ref. 3). HEART CAN'T SYNTHESIZE DOCOSAHEXAENOIC ACID FROM CIRCULATING ALPHA-LINOLENIC ACID BECAUSE IT LACKS ELONGASE-2 Dietary supplementation with long-chain PUFAs, including DHA, reduces the incidence of sudden cardiac death. The rat heart, however, cannot convert alpha-LA to longer-chain DHA (22:6n-3) because it lacks a critical enzyme, elongase 2. It must obtain its DHA entirely from dietary sources or by liver synthesis from alpha-LNA. Dietary n-3 PUFA deprivation in the rat reduces heart DHA and increases heart docosapentaenoic acid (22:5n-6), which may increase vulnerability to ischemia (Ref. 4). ARACHIDONIC ACID AND THE BRAIN We reviewed how arachidonic acid participates in neurotransmission in the mammalian brain, and how its metabolism is disturbed in neuroinflammation and excitotoxicity (Ref. 5). FATTY ACID COMPOSITION OF WILD ANTHROPOID PRIMATE MILK Anthropoid primates vary in growth, development and brain size. In collaboration with scientists at the National Zoo, we found that milk from leaf eating species had a higher proportion of alpha-LA (18:3n-3) than did milk from omnivores. Mountain gorillas had a uniquely high proportion of milk AA (20:4n-6). The differences were unrelated to brain size, and reflected species metabolic differences and/or differences in diet (Ref. 7).